Complex lasso proteins

File:Lasso types.png

Complex lassos can be divided according to the number of piercings through the minimal surface spanned on the covalent loop.{{Cite journal|last1=Niemyska|first1=Wanda|last2=Dabrowski-Tumanski|first2=Pawel|last3=Kadlof|first3=Michal|last4=Haglund|first4=Ellinor|last5=Sułkowski|first5=Piotr|last6=Sulkowska|first6=Joanna I.|date=2016-11-22|title=Complex lasso: new entangled motifs in proteins|journal=Scientific Reports|volume=6|issue=1|pages=36895|doi=10.1038/srep36895|issn=2045-2322|pmc=5118788|pmid=27874096|bibcode=2016NatSR...636895N}}{{Cite journal|last1=Dabrowski-Tumanski|first1=Pawel|last2=Niemyska|first2=Pawel|last3=Pasznik|first3=Pawel|last4=Sulkowska|first4=Joanna I.|date=2016-04-29|title=LassoProt: server to analyze biopolymers with lassos|journal=Nucleic Acids Research|volume=44|issue=W1|pages=W383–W389|doi=10.1093/nar/gkw308|pmid=27131383|issn=1362-4962|pmc=4987892}} In particular, four classes of complex lasso proteins exist:

• the L_n class (simple lasso), where one tail pierces the surface n times;
• the LS_n class (the supercoiling lasso), where one tail pierces the surface n times, winding around the loop;
• the LL_i,j class (double lasso), where both tails pierce the surface i and j times respectively;
• the LSL_i,j class, where one tail pierces the surface i times in the supercoiling manner, and the second pierces the surface in the simple manner.

Another classification may be given according to the nature of the bridge closing the covalent loop. Most of the complex lasso proteins have a disulfide-based loop, however, the amide-based (lasso peptides) and ester-based complex lasso proteins are also known.

Complex lassos can coexist with other protein topologies. An analysis performed on the structures predicted by the AlphaFold found examples of knotted lasso proteins.{{Cite journal |last=da Silva |first=Fernando Bruno |last2=Perlinska |first2=Agata P. |last3=Płonka |first3=Jacek |last4=Flapan |first4=Erica |last5=Sulkowska |first5=Joanna I. |date=2025-05-19 |title=Universe of Lasso Proteins: Exploring the limit of entanglement of protein predicted by AlphaFold |url=https://linkinghub.elsevier.com/retrieve/pii/S0022283625002839 |journal=Journal of Molecular Biology |pages=169217 |doi=10.1016/j.jmb.2025.169217 |issn=0022-2836}} The knots were present not only on the tail part of the lasso, but also on the loop itself. These motifs can be found in the membrane proteins.

Around 18% of proteins with disulfide bridges have complex lasso, however, much more complex lasso would be predicted when analyzing the non-interacting polymeric models.{{Cite journal|last1=Dabrowski-Tumanski|first1=Pawel|last2=Gren|first2=Bartosz|last3=Sulkowska|first3=Joanna I.|date=2019-04-17|title=Statistical Properties of Lasso-Shape Polymers and Their Implications for Complex Lasso Proteins Function|journal=Polymers|volume=11|issue=4|pages=707|doi=10.3390/polym11040707|pmid=30999683|pmc=6523798|issn=2073-4360 |doi-access=free }} Apart from structures with only one pierced loop, there may be also chains with several complex lasso structures. In particular, the loops may pierce each other, forming a protein Hopf link.{{Cite journal|last1=Dabrowski-Tumanski|first1=Pawel|last2=Sulkowska|first2=Joanna I.|date=2017-03-28|title=Topological knots and links in proteins|journal=Proceedings of the National Academy of Sciences|volume=114|issue=13|pages=3415–3420|doi=10.1073/pnas.1615862114|issn=0027-8424|pmc=5380043|pmid=28280100 |doi-access=free }} There are much less complex lassos in proteins than it is expected from simple polymer models. However, there are groups of proteins which have higher complex lasso probability than we could expect from such models.

Over 2.2 million complex lasso motifs were found in the AlphaFold-predicted proteins. The result of this search is available in the database section of the [https://alphalasso.cent.uw.edu.pl AlphaLasso] web server.

It is not known if the complex lasso motif is functional in general. However, in some cases the importance of the motif for the protein function was reported. In particular, in case of lasso peptides, the motif allows to act like a plug for specific NTP-uptake channels.{{Cite journal|last1=Knappe|first1=Thomas A.|last2=Linne|first2=Uwe|last3=Zirah|first3=Séverine|last4=Rebuffat|first4=Sylvie|last5=Xie|first5=Xiulan|last6=Marahiel|first6=Mohamed A.|date=August 2008|title=Isolation and Structural Characterization of Capistruin, a Lasso Peptide Predicted from the Genome Sequence of Burkholderia thailandensis E264|journal=Journal of the American Chemical Society|volume=130|issue=34|pages=11446–11454|doi=10.1021/ja802966g|pmid=18671394|s2cid=5327111 |issn=0002-7863}}{{Cite journal|last1=Pan|first1=Si Jia|last2=Link|first2=A. James|date=2011-04-06|title=Sequence Diversity in the Lasso Peptide Framework: Discovery of Functional Microcin J25 Variants with Multiple Amino Acid Substitutions|journal=Journal of the American Chemical Society|volume=133|issue=13|pages=5016–5023|doi=10.1021/ja1109634|pmid=21391585|issn=0002-7863}}{{Cite journal|last1=Hegemann|first1=Julian D.|last2=Zimmermann|first2=Marcel|last3=Xie|first3=Xiulan|last4=Marahiel|first4=Mohamed A.|date=2015-07-21|title=Lasso Peptides: An Intriguing Class of Bacterial Natural Products|journal=Accounts of Chemical Research|volume=48|issue=7|pages=1909–1919|doi=10.1021/acs.accounts.5b00156|pmid=26079760|issn=0001-4842}} The motif has also shown significant inhibitory activities against cancer cell invasion and migration.{{Cite journal |last=Son |first=Sangkeun |last2=Jang |first2=Mina |last3=Lee |first3=Byeongsan |last4=Hong |first4=Young-Soo |last5=Ko |first5=Sung-Kyun |last6=Jang |first6=Jae-Hyuk |last7=Ahn |first7=Jong Seog |date=2018-10-26 |title=Ulleungdin, a Lasso Peptide with Cancer Cell Migration Inhibitory Activity Discovered by the Genome Mining Approach |url=https://pubs.acs.org/doi/10.1021/acs.jnatprod.8b00449 |journal=Journal of Natural Products |language=en |volume=81 |issue=10 |pages=2205–2211 |doi=10.1021/acs.jnatprod.8b00449 |issn=0163-3864|url-access=subscription }} However, multiple cyclized isomers of the peptide display this migration inhibition, suggesting the function arises from the cyclization of the peptide and not the lasso motif.{{Cite journal |last=Digal |first=Lori |last2=Samson |first2=Shiela C. |last3=Stevens |first3=Mark A. |last4=Ghorai |first4=Abhijit |last5=Kim |first5=Hyungyu |last6=Mifflin |first6=Marcus C. |last7=Carney |first7=Keith R. |last8=Williamson |first8=David L. |last9=Um |first9=Soohyun |last10=Nagy |first10=Gabe |last11=Oh |first11=Dong-Chan |last12=Mendoza |first12=Michelle C. |last13=Roberts |first13=Andrew G. |date=2024-01-19 |title=Nonthreaded Isomers of Sungsanpin and Ulleungdin Lasso Peptides Inhibit H1299 Cancer Cell Migration |url=https://pubs.acs.org/doi/10.1021/acschembio.3c00525 |journal=ACS Chemical Biology |language=en |volume=19 |issue=1 |pages=81–88 |doi=10.1021/acschembio.3c00525 |issn=1554-8929|pmc=11832225 }} On the other hand, the motif was shown to be functional in case of leptin - the obesity-related protein.{{Cite journal|last1=Haglund|first1=Ellinor|last2=Pilko|first2=Anna|last3=Wollman|first3=Roy|last4=Jennings|first4=Patricia Ann|last5=Onuchic|first5=Jose Nelson|date=2016-12-30|title=Pierced Lasso Topology Controls Function in Leptin|journal=The Journal of Physical Chemistry B|volume=121|issue=4|pages=706–718|doi=10.1021/acs.jpcb.6b11506|pmid=28035835|s2cid=4680168 |url=http://www.escholarship.org/uc/item/62z7s7v0}} The analysis of the shape of complex lasso proteins compared to the polymeric models with similar size shows, that some classes of complex lasso proteins may also be functional. This concerns toxic, antimicrobial, defensin-like or immune system related with L₁ motif

The current list of experimentally obtained complex lasso proteins may be found in the [http://lassoprot.cent.uw.edu.pl LassoProt] database, which allows also uploading and analyzing own data. The [https://alphalasso.cent.uw.edu.pl AlphaLasso] web server enables analysis of AI-predicted protein structures and provides a database of disulfide-based loops in the AlphaFold-predicted models.{{Cite journal |last=Rubach |first=Pawel |last2=Płonka |first2=Jacek |last3=Gren |first3=Bartosz A. |last4=Bruno da Silva |first4=Fernando |last5=Korpacz |first5=Marta |last6=Sulkowska |first6=Joanna I. |date=2025-05-07 |title=AlphaLasso—a web server to identify loop and lasso motifs in 3D structure of biopolymers |url=https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkaf375/8126259 |journal=Nucleic Acids Research |pages=gkaf375 |doi=10.1093/nar/gkaf375 |issn=1362-4962|doi-access=free }} The manual inspection of the data is also possible with the [http://pylasso.cent.uw.edu.pl PyLasso]{{Cite journal|last1=Gierut|first1=Aleksandra M|last2=Niemyska|first2=Wanda|last3=Dabrowski-Tumanski|first3=Pawel|last4=Sułkowski|first4=Piotr|last5=Sulkowska|first5=Joanna I|date=2017-12-01|editor-last=Valencia|editor-first=Alfonso|title=PyLasso: a PyMOL plugin to identify lassos|journal=Bioinformatics|volume=33|issue=23|pages=3819–3821|doi=10.1093/bioinformatics/btx493|pmid=28961868|issn=1367-4803|doi-access=free}} - a PyMol plugin.

Knotted proteins

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Category:Peptides

Category:Biosynthesis